Synthesis of tryptophan-dehydrobutyrine diketopiperazine and biological activity of hangtaimycin and its co-metabolites

Abstract

An improved synthesis for tryptophan-dehydrobutyrine diketopiperazine (TDD), a co-metabolite of the hybrid polyketide/non-ribosomal peptide hangtaimycin, starting from ʟ-tryptophan is presented. Comparison to TDD isolated from the hangtaimycin producer Streptomyces spectabilis confirmed its S configuration. The X-ray structure of the racemate shows an interesting dimerisation through hydrogen bridges. The results from bioactivity testings of hangtaimycin, TDD and the hangtaimycin degradation product HTM222 are given.

Concise Synthesis of 2,5-Diketopiperazines via Catalytic Hydroxy-Directed Peptide Bond Formations

“…In the nature, various DKPs have an exo-olefin group, such as Cyclo­(Deala- l -Leu) ( 11 ), tryptophan-dehydrobutyrine diketopiperazine, or maremycin, and we anticipated that their framework could be derived from DKPs with hydroxymethyl functional groups. Thus, we attempted to demonstrate the transformation of Cyclo­(Ser–Leu) ( 4a ) to the Cyclo­(Deala- l -Leu) ( 11 ) (Scheme ).…”

Methylation in hangtaimycin biosynthesis and its antibacterial activities

“…As has been demonstrated, a cytochrome P450 monooxygenase in HTM biosynthesis is responsible for the C-42 oxidation of deoxyhangtaimycin to HTM [ 14 ]. The installed hemiaminal functionality is unstable and easily lead to the degradation of HTM into HTM 222 and a larger lactone-polyene peptide fragment [ 16 ]. Another HTM cometabolite in S. spectabilis is tryptophan-dehydrobutyrine diketopiperazine (TDD), which had been isolated for several decades ahead of HTM, but its absolute configuration was confused [ [17] , [18] , [19] ].…”

“…Another HTM cometabolite in S. spectabilis is tryptophan-dehydrobutyrine diketopiperazine (TDD), which had been isolated for several decades ahead of HTM, but its absolute configuration was confused [ [17] , [18] , [19] ]. In HTM biosynthesis, HTM and TDD was found to be simultaneous disappearance and appearance, suggesting the same set of biosynthetic machinery for HTM [ 16 , 19 ]. The formation mechanism of TDD is still unknown, in our opinion, it may be formed by an unidentified enzyme in HTM's biosynthesis.…”

“…The formation mechanism of TDD is still unknown, in our opinion, it may be formed by an unidentified enzyme in HTM's biosynthesis. Recently, Xu et al had established the S configuration for the natural product TDD from S. spectabilis by comparing with synthetic standard, which is likely reflected in the corresponding portion of HTM, for the reason of absence of E domain in HTM biosynthesis [ 16 ]. To further confirm that the formation of TDD and HTM 222 could be part of the cause of the degradation of HTM ( Fig.…”